Rasagiline is a chemical inhibitor of enzyme monoamine oxidase (MAO) type B which has a major role in the inactivation of biogenic and diet derived amines in the central nervous system. MAO has two isozymes (types A and B) and type B is responsible for metabolising dopamine in the central nervous system; as dopamine deficiency is the main contributing factor to the clinical manifestations of Parkinson's disease, inhibition of MAO-B should tend to restore dopamine levels towards normal values and this improves the condition. Rasagiline was developed for the symptomatic treatment of Parkinson's disease both as monotherapy in early disease and as adjunct therapy to levodopa+aminoacids decarboxylase inhibitor (LD+ADI) in patients with motor fluctuations. Parkinson's disease is a common neurodegenerative disorder typified by loss of dopaminergic neurones from the basal ganglia and by a characteristic clinical syndrome with cardinal physical signs of resting tremor, bradikinesia and rigidity. The main treatment aims at alleviating symptoms through a balance of anti-cholinergic and dopaminergic drugs.
Rasagiline mesylate, chemically known as 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate or N-propargyl-1(R)-aminoindan mesylate, is approved for the treatment of Parkinson's disease and marketed under the name AZILECT® by Teva. Scientific discussion for Azilect states that two salts were used during the non-clinical programme. Initially the hydrochloride salt was used but this was changed to the mesylate salt to overcome stability issues. Inhibition of MAO activity by rasagiline mesylate, rasagiline hydrochloride, their (S)-isomers and by the metabolite, 1-(R)-aminoindan hydrochloride was studied in vitro and ex vivo. Both Rasagiline mesylate and Rasagiline hydrochloride exhibit a similar, highly potent and MAO-B-selective inhibition activity in vitro.
EP436492 discloses process for preparation of R-(+)-Rasagiline hydrochloride which involves reaction of racemic 1-aminoindan (2) with propargyl chloride (6) in presence of potassium carbonate in acetonitrile (ACN) at 60° C. for 16 hours to obtain racemic Rasagiline base (4) which is purified using column chromatography. The ethereal solution of purified racemic base is then treated with HCl gas followed by recrystallization using isopropanol (IPA) to obtain racemic Rasagiline hydrochloride (7). R-(+)-Rasagiline is separated from the obtained racemic Rasagiline base (4) by preparative HPLC chromatography and further converted to its hydrochloride salt.

Another process for preparation of Rasagiline hydrochloride as disclosed in EP '492 comprises reaction of R(−)-1-aminoindan (8) with propargyl chloride (6) in presence of potassium carbonate in acetonitrile (ACN) at 60° C. for 16 hours to obtain R(+) Rasagiline base (9) which is then purified by column chromatography. The purified base is then converted to R(+)-Rasagiline hydrochloride followed by recrystallization with isopropanol. The main disadvantage of this process is longer reaction time (16 hours) and low overall yield of about 56%.

U.S. Pat. No. 3,513,244 and U.S. Pat. No. 5,532,415 disclose process for preparation of Rasagiline hydrochloride.
U.S. Pat. No. 5,532,415 discloses process for preparation of R(+)-Rasagiline mesylate which comprises treating a solution of propargyl benzenesulfonate (3) and racemic aminoindan (2) in toluene with aqueous solution of 15% sodium hydroxide to get racemic Rasagiline base (4). The obtained crude racemic Rasagiline is treated with L-tartaric acid in isopropanol (IPA) to get di(R-(+)-N-propargyl-1-aminoindan)-L-tartrate (5) which is recrystallized from 1:1 methanol/isopropanol. The obtained tartrate salt is reacted with methanesulphonic acid in isopropanol at reflux to obtain R(+)-Rasagiline mesylate. The disadvantage of this process is that the scheme consists of low atom efficiency and involves several steps to obtain the final product.

WO2006091657 discloses solid pharmaceutical formulations of Rasagiline salt comprising a mixture of particles of a pharmaceutically acceptable salt of Rasagiline, wherein more than 90% of the total amount by volume of Rasagiline salt particles have a size of less than 250 microns. It is further disclosed that at least 90% of the total amount by volume of Rasagiline salt particles have a size greater than 6 microns (particle size determination by wet method).
WO2009122301 discloses Rasagiline mesylate having 90 volume-percent of the particles (D90) with a size of about 600 microns to 1500 microns (particle size determination by wet method) and process for its preparation.
WO2010059913 describes processes for the preparation of Rasagiline mesylate comprising reacting 1-indanone with propargylamine or a salt thereof in the presence of a solvent to afford N-(2-propynyl)-indanylimine or a salt thereof which is optionally isolated. The obtained N-(2-propynyl)-indanylimine or a salt thereof is reduced with a reducing agent to afford racemic Rasagiline. The obtained racemic Rasagiline is treated with chiral resolving agent to get diastereomeric salt; optionally isolating the free base of diastereomeric salt. The obtained free base or diastereomeric salt is reacted with acid in solvent to get acid addition salt of R(+)-Rasagiline. WO '913 also discloses Rasagiline mesylate having 90 volume percent of the particles (D90) with sizes less than about 6 μm and processes for the preparation thereof.
U.S. Pat. No. 7,491,847 discloses methods of isolation of secondary propargylated aminoindan derivatives from a reaction mixture.
There exists a need to develop a simple and commercially viable process for the preparation of R(+)-Rasagiline and its salts. The present invention provides industrially viable process for preparation of R(+)-Rasagiline or pharmaceutically acceptable salt thereof, such as mesylate, hydrobromide and hydrochloride salt of Rasagiline in high yield and purity. The inventors of the present invention have studied the various salts of Rasagiline. It is known that salts of active pharmaceutical ingredients (APIs) are used in drug formulations because of improved properties with respect to solubility, stability or bioavailability. The present invention deals with a novel salt of R(+)-Rasagiline, R(+)-Rasagiline palmitate and process for preparation thereof.
The inventors of the present invention have also studied polymorphism in Rasagiline and its salts. Polymorphism is the ability of a compound to exhibit more than one orientation or conformation of molecules within the crystal lattice. Many organic compounds, including active pharmaceutical ingredient (API), exhibit polymorphism. Drug substances may exist in various polymorphic forms, which may differ from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties, thus affecting dissolution, bioavailability and handling characteristics of the substance. Rate of dissolution of an API in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administrated API can reach the patient's bloodstream. Flowability affects the ease with which the material is handled while processing a pharmaceutical product. Knowledge of the existence of different crystal phases and their overall physical and chemical behavior is required for selection of a polymorphic form for use in the preparation of a final dosage form. It is preferred to have a single, pure and stable polymorphic form in the final drug product. To this end, investigation of crystal polymorphism is an essential step in pharmaceutical research due to the influence of solid-state properties on dosage form. The present invention provides polymorphs of R-(+)-Rasagiline hydrochloride and process for preparation thereof. Polymorphic forms of R-(+)-Rasagiline hydrochloride of the present invention have good flow properties, especially good bulk flow properties suitable for pharmaceutical formulation.